Sustained release eye drop formulations

ABSTRACT

This invention provides for biocompatible, biodegradable eye drop pharmaceutical formulations useful for the treatment of ocular indications. In particular, tocopherols and their esters of low water solubility, notably α-tocopheryl acetate, are exceptional vehicles for biocompatible, nonirritating topical eye drop formulations that provide sustained release of active agents.

RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §119(e) of U.S.patent application Ser. No. 60/690,315, filed Sep. 25, 2007, entitledSustained Release Eye Drops and Conveniently Implantable SustainedRelease Drug Formulations, by Vernon G. Wong and Louis L. Wood, and is acontinuation-in-part of U.S. patent application Ser. No. 11/826,833,filed Jul. 17, 2007, which claims the benefit under 35 U.S.C. §119(e) ofU.S. patent application Ser. No. 60/831,991, filed Jul. 19, 2006, whichis a continuation-in-part and claims the benefit under 35 U.S.C. §120 ofU.S. patent application Ser. No. 11/236,426, filed Sep. 27, 2005, whichis related to and claims the benefit under 35 U.S.C. §119(e) of U.S.patent application Ser. No. 60/709,665, filed Aug. 19, 2005, and Ser.No. 60/614,484, filed Oct. 1, 2004, each entitled ConvenientlyImplantable Sustained Release Drug Compositions, by Vernon G. Wong andLouis L. Wood. Each of the foregoing applications is incorporated in itsentirety herein.

FIELD OF THE INVENTION

The present invention relates to the field of ophthalmology involvingbiocompatible, biodegradable, sustained-release formulations ofbeneficial, active agents for topical administration to the eye.

BACKGROUND OF THE INVENTION

Current topical eye drop formulations, in addition to often elicitingsome degree of transient irritation, provide only short term exposure ofbeneficial agents to the eye and thus often require severaladministrations daily. Other modes of drug delivery, such as oraldelivery and injection, may result in high and low blood concentrationsand/or shortened half-life in the blood, in addition to systemicdelivery of medicaments that are only required in the eye. In somecases, achieving therapeutic efficacy with these standardadministrations requires large doses of medications that may result intoxic side effects. Additionally, some eye drop formulations areunstable over the normal period of treatment, which may be exacerbatedby patient mis-handling. The technologies relating to controlled drugrelease have been attempted in an effort to circumvent some of thepitfalls of conventional therapy. Their aims are to deliver medicationson a continuous and sustained manner.

There remains a need for a more economical, practical, and efficient wayof producing and manufacturing drug delivery systems that may be usedlocally, in liquid, gel, or ointment formulations. In particular, thereremains a need for sustained-release formulations for topicaladministrations (eye drops) of beneficial, active agents to the eye.

SUMMARY OF THE INVENTION

An object of the present invention provides for economical, practical,and efficient drug delivery systems. According to the present invention,this drug delivery system is produced easily, delivered easily to thesite of indication, and is both biocompatible and biodegradable. Inother words, the biocompatible, biodegradable formulations of thepresent invention disappear harmlessly after delivering active agent tothe desired site. The formulations of the present invention provide fornovel therapies that are easily used by qualified medical practitionersas well as by subjects in need thereof. The formulations delivertherapeutic and non-toxic levels of active agents over the desiredextended time frame, often primarily at the site of administration.

The embodiments of the present invention provide for formulations fortopical administrations of active agents to the eye. The presentinvention provides for eye drop formulations comprising at least oneactive agent in a biocompatible, biodegradable excipient that sustainsthe release of the active agent, and which may be chosen from tocopherolisomers and/or their esters; and tocotrienols and/or their esters, suchas d, l and dl isomers of α, β, δ, ε, η tocopherols and similar isomersof the tocotrienols and the esters of these tocopherols and tocotrienolswith straight and branched chain C2 to C20 aliphatic acids, or theiresters of C3 to C20 straight chain dicarboxylic acids; the mono, di, andtri esters of O-acetylcitric acid or O-propionylcitric acid orO-butyrylcitric acid with C1 to C10 straight and branched chainaliphatic alcohols; the mono, di, and tri esters of citric acid with C1to C10 straight and branched chain aliphatic alcohols. In anotherembodiment of the invention, the active agent or excipient may be anomega-3 fatty acid or an ester thereof Another embodiment of the presentinvention provides for a formulation comprising a nonpolymeric,biodegradable, bioabsorbable excipient and the active agent is one ormore antioxidants, either alone or included with one or more steroidsand/or quinolone anti-infectives. Typically, the formulations of thepresent invention provide for the sustained release of the active agentfor at least four days.

The active agent envisioned in an embodiment of the present invention isat least one agent of the analgesics, anesthetics, narcotics,angiostatic steroids, anti-inflammatory steroids, angiogenesisinhibitors, nonsteroidal anti-inflammatories, anti-infective agents,antibiotics, antifungals, antivirals, alpha androgenergic agonists, betaadrenergic blocking agents, carbonic anhydrase inhibitors, mast cellstabilizers, miotics, prostaglandins, antihistamines, antimicrotubuleagents, antineoplastic agents, antipoptotics, aldose reductaseinhibitors, antihypertensives, antioxidants, growth factor agonists andantagonists, vitrectomy agents, adenosine receptor antagonists,adenosine deaminase inhibitors, glycosylation antagonists, anti-agingpeptides, topoisemerase inhibitors, anti-metabolites, alkylating agents,oncogene activation inhibitors, telomerase inhibitors, antibodies orportions thereof, fusion proteins, tyrosine kinase inhibitors,ribonucleotide reductase inhibitors, cytotoxins, IL2 therapeutics,neurotensin antagonists, peripheral sigma ligands, endothelinETA/receptor antagonists, antihyperglycemics, anti-glaucoma agents,anti-chromatin modifying enzymes, insulins, glucagon-like-peptides,immunosuppressive agents, tissue repair agents, essential fatty acids,and nucleic acids such as antisense oligonucleotides, siRNA or RNAi.

In another aspect of the present invention, more than one biodegradable,biocompatible excipient may be used to facilitate sustained release ofan active agent. For example, a relatively small amount of a tocopherol,such as α tocopheryl acetate, may be added to a mixture of omega-3 fattyacid and prednisolone, increasing the sustained release of prednisolonefrom the formulation.

In particular embodiments, the eye drop formulation consists of αtocopheryl acetate and cyclosporin A, rapamycin, or timolol, or aprostaglandin. In another embodiment of the invention, the eye dropformulation consists of α tocopheryl acetate and latanoprost.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts dissolution profiles of dexamethasone (Dex) released fromthree formulations of Dex/d-tocopherol, and dl-tocopheryl acetate.

FIG. 2 shows cyclosporin A (CSA) release in rabbit tears followinginstallation of one drop of a 45:55 (wt) CSA:α-tocopheryl acetate (EA)formulation.

FIG. 3 shows timolol release in rabbit tears following installation ofone drop of a 10:90 (wt) timolol:dl-tocopheryl acetate (EA) formulation.

FIG. 4 depicts Dex release from two different formulations ofDex:d-tocopherol and one formulation of Dex:dl-tocopherol acetate.

FIGS. 5A-5D are charts showing the intraocular pressure of two rabbitstreated with a saline in one eye; and a formulation of latanaprost indl-tocopheryl acetate in the other eye.

FIG. 6 depicts the percent Dex released in vitro from a formulation of24% Dex and Triethyl O-Acetyl Citrate (TEAC).

FIG. 7 shows the percent Dex released in vitro from a formulation of 20%Dex and TEAC/Tocopheryl acetate.

DETAILED DESCRIPTION OF THE INVENTION

It should be understood that this invention is not limited to theparticular methodology, protocols, and reagents, etc., described hereinand as such may vary. The terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to limit thescope of the present invention, which is defined solely by the claims.

As used herein and in the claims, the singular forms “a,” “an,” and“the” include the plural reference unless the context clearly indicatesotherwise. Thus, for example, the reference to an excipient is areference to one or more such excipients, including equivalents thereofknown to those skilled in the art. Other than in the operating examples,or where otherwise indicated, all numbers expressing quantities ofingredients or reaction conditions used herein should be understood asmodified in all instances by the term “about.”

All patents and other publications identified are incorporated herein byreference for the purpose of describing and disclosing, for example, themethodologies described in such publications that might be used inconnection with the present invention, but are not to providedefinitions of terms inconsistent with those presented herein. Thesepublications are provided solely for their disclosure prior to thefiling date of the present application. Nothing in this regard should beconstrued as an admission that the inventors are not entitled toantedate such disclosure by virtue of prior invention or for any otherreason. All statements as to the date or representation as to thecontents of these documents is based on information available to theapplicants and do not constitute any admission as to the correctness ofthe dates or contents of these documents.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as those commonly understood to one of ordinaryskill in the art to which this invention pertains.

The present invention relates to novel biocompatible, biodegradablesustained release topical formulations suitable for administration tothe eye. In various aspects of the invention these formulations areliquids, gels, ointments, or emulsified micells (oil in water or waterin oil). The formulations include at least one active agent which isdelivered in a limited solubility, biocompatible, biodegradable (oftenreferred to herein as LSBB) formulation. The LSBB formulations of thepresent invention deliver therapeutic and non-toxic levels of activeagents over the desired extended time frame. These formulations are bothbiocompatible and biodegradable, and disappear harmlessly afterdelivering active agent.

The present invention provides for sustained release eye dropformulations for topical administrations of beneficial, active agents tothe eye. Topical eye drops are directed generally to therapies for theanterior segments of the eye, which are the contemplated therapies forthe formulations of this invention, The anterior segment includes theanterior chamber, iris, ciliary body, lens, and the eye surface. The eyesurface is composed of the cornea, conjunctiva, eye lids, lacrimal andmeibomian glands, and the interconnecting nerves. The tocopherols andtheir esters of low water solubility, notably α-tocopheryl acetate, areexceptional vehicles for biocompatible, nonirritating topical eye dropformulations providing sustained release of beneficial agents forperiods of at least about four days from a single application withoutinterfering with vision.

Specific areas of the human or animal body to be targeted for topicalapplications of the excipient/active agents LSBB compositions include,but are not limited to: eyes, punctum lacrimale (tear ducts), nasalpassages, mucosa of the nasal cavity and throat, The formulationsaccording to the present invention have particular applicability inproviding a controlled and sustained release of active agents effectivein obtaining a desired local or systemic physiological orpharmacological effect relating at least to the treatment of eyeinfections, or modification of the immune response, such as preventingand treating transplant rejection, and providing therapy for chronic dryeye syndrome.

More specifically, the LSBB formulations are useful for treating ocularconditions such as glaucoma, PVR, diabetic retinopathy, uveitis, retinaledema, vein occulusion, macular degeneration. Irvine-Gass Syndrome andCMV retinitis, corneal diseases such as keratitis, and cornealtransplantation rejection by mediating homograft rejection withformulations comprising sirolimus or cyclosporine. The formulations mayalso be prepared as control-release eye drops for dry-eye or forcontrolling the immune response. Regarding control of immune responses,the formulations may contain one or more of cyclosporine, sirolimus, ortacrolimus. Other intraocular uses include glaucoma treatments (e.g.,formulations including timolol or prostaglandins such as latanoprost),antibiotic delivery, antibody delivery, and antiproliferatives delivery(e.g., paclitaxel).

Additional maladies of the ocular tissues that may be treated with theformulations of the present invention include eye lid indications suchas hordeolum, chalazaion, rosacea, blepharitis, squamous, and basalcarcimona. Corneal indications include corneal infections, dry eye,Fuchs' dystrophy, herpes zoster (shingles), iridocorneal endothelialsyndrome, keratoconus, lattice dystrophy, map-dot-fingerprint dystrophy,herpes simplex, pterygium, Stevens-Johnson Syndrome, acute or chronicfocal immunological corneal graft reaction or rejection and followingany corneal transplant procedures. Diseases of the lacrimal glandsinclude allergic, inflammatory, infectious, traumatic, malignant, andautoimmune diseases. Conjunctival indications include conjunctivitis(pink eye, allergic, bacterial, viral, giant papillary,keratoconjunctivits, inclusion), neoplasms (dermoid cysts, squamous cellcarcinoma of the conjunctiva, papilloma, acquired melanosis of theconjunctiva, malignant melanoma of the conjunctiva, nevus of theconjunctiva, vascular tumors), pterygium and pinguecula, xerophalmia,subconjuctival hemorrhage, dry-eye syndrome, and Sjögren's syndrome.Glaucoma indications are open-angle glaucoma and narrow angle glaucomaand neovascular glaucoma. Diseases of the iris include albinism,aniridia, coloboma, iritis, melanoma, metastases and Waardenburgsyndrome, and epithelial cysts. Surgical indications are anypost-surgical inflammatory and infection induced by Lasik cornealprocedures, cataract extraction, glaucoma surgery, conjunctival and/ormucous membrance transplantation. Other ocular maladies to be consideredinclude exophthalmos, scleritis, episcleritis, Grave's disease,pseudotumor of the orbit, lymphoma of the orbit, tumors of the orbit,orbital cellulitis, pre-phthisical ocular hypotomy, neovascularglaucoma, and anterior uveitis of inflammatory or infectious etiology.

Further regarding corneal indications, an aspect of the inventionprovides for a formulation for limiting tissue rejection followingcorneal transplant. Corneal transplant, also known as a corneal graft orpenetrating keratoplasty, involves the removal of the central portion(called a ‘button’) of the diseased cornea and replacing it with amatched donor button of cornea. Corneal grafts are performed on patientswhose damaged or scarred corneas (a result of disease or trauma),prevent acceptable vision. Formulations of the present invention usefulin corneal transplant contexts may include rapamycin, cyclosporin, or acombination of these active agents.

Some common types of beneficial agents administered by topical eye dropsfor treatment of the maladies of the eye and contemplated for theformulations of the present invention include β-blockers, prostaglandinanalogs, α2-adrenergic agonists, miotic agents, sympathomimetics,carbonic anhydrase inhibitors, antibiotics, steroidalanti-inflammatories, NSAIDs, antihistamines, immunsuppressive agents,and lubricants.

Further regarding glaucoma or increased intraocular pressure, medicationclasses historically used in the management of glaucoma include betablockers, miotics, sympathomimetics and carbonic anhydrase inhibitors.Because topically applied medications are more site-specific, they arepreferred in the treatment of glaucoma. Compared with oral medications,topical agents are associated with a decreased incidence of systemicside effects. With current topical formulations, conjunctival andlocalized skin allergic reactions are fairly common, whereas severereactions, including death, are rare. Recently introduced topical agentsfor glaucoma therapy include dorzolamide and brinzolamide, the firsttopical carbonic anhydrase inhibitors; brimonidine and apraclonidine,more ocular-specific alpha agonists; and latanoprost, a prostaglandinanalog, which is a new class of glaucoma medication. Like theirpredecessors, the newer agents lower intraocular pressure by astatistically significant degree. Preservation of visual field, the moresubstantial patient-oriented end point, continues to be studied. Anexample formulation of the present invention, particularly useful forlowering intraocular pressure, consists of α tocopheryl acetate and theprostaglandin, latanoprost. In vivo, eye drops consisting ofprostaglandin and tocopheryl acetate, applied once weekly, maintainedlow intraocular pressure in rabbit eyes for at least three months.

A wide variety of other disease states are known by those of ordinaryskill in the art, such as those described in Goodman & Gilman, THEPHARMACOLOGICAL BASIS OF THERAPEUTICS (McGraw Hill, 2001), andREMINGTON'S PHARMACEUTICAL SCIENCES (Lippincott Williams & Wilkins; 20thed., 2000). Those to which the present invention may be applied may bedetermined by those with ordinary skill in the art without undueexperimentation.

Suitable classes of active agents for use in the system of the presentinvention include, but are not limited to: Peptides and proteins such ascyclosporin, insulins, glucagon-like-peptides, growth hormones, insulinrelated growth factor, botulinum toxins (Botox, Allergan), antibodies,and heat shock proteins; Anesthetics and pain killing agents such aslidocaine and related compounds, and benzodiazepam and relatedcompounds; Anti-cancer agents such as 5-fluorouracil, methotrexate andrelated compounds; Anti-inflammatory agents such as 6-mannose phosphate;Anti-fungal agents such as fluconazole and related compounds; Antiviralagents such as trisodium phosphomonoformate, trifluorothymidine,acyclovir, cidofovir, ganciclovir, ddI, and AZT; Cell transport/mobilityimpeding agents such as colchicines, vincristine, cytochalasin B, andrelated compounds; Anti-glaucoma drugs such as beta-blockers: timolol,betaxolol, and atenolol; Immunological response modifiers such asmuramyl dipeptide and related compounds; Steroidal compounds such asdexamethasone, prednisolone, triamcinolone and related compounds; andCarbonic anhydrase inhibitors such as acetazolamide, brinzolamide,dorzolamide, and timolol maleate.

In addition to the above agents, other active agents which are suitablefor administration, especially to the eye and its surrounding tissues,to produce a local or a systemic physiologic or pharmacologic effect canbe used in the system of the present invention. Examples of such agentsinclude antibiotics such as tetracycline, chloramphenicol,ciprofloxacin, ampicillin, and the like.

The present formulations provide for the use of formulations comprisingexcipients characterized as of limited solubility, biocompatible, andbiodegradable (LSBB), for controlled and sustained release of an activeagent or a combination of active agents. Liquid or gelcontrolled-sustained release systems can be fabricated by combining anLSBB excipient and an active agent. Formulations may include more thanone biodegradable component as well as more than one active agent. Gelscan be produced by vortex or mechanical mixing. Liquid formulations canbe made by pre-mixing in a suitable container, or mixing of theexcipient and the active agent before or at the time of administration.A typical method of mixing an excipient and active agent usessonication.

As noted, the excipient of the present invention is biodegradable orbioerodible. As used herein, the terms “bioerodible” and “biodegradable”are equivalent and are used interchangeably. Biodegradable excipientsare those which degrade in vivo, and wherein erosion of the excipientover time is required to achieve the agent release kinetics according tothe invention.

The excipient is also biocompatible, meaning that it does not have unduetoxicity or cause either physiologically or pharmacologically harmfuleffects. In the context of topical formulations for the eye, it shouldbe understood that some initial “stinging” or minor discomfort is commonwith eye drops, but such minor reactions do not render the presentformulations non-biocompatible.

In an aspect of the present invention, the novel biocompatible andbiodegradable liquid and gel formulations, which may be convenientlytopically placed on the human or animal eye for the sustained release ofactive agent(s), are obtained by admixing one or more excipients, suchas, for example: d, l and dl isomers of α, β, δ, ε, η tocopherols andsimilar isomers of the tocotrienols and the esters of these tocopherolsand tocotrienols with straight and branched chain C2 to C20 aliphaticacids, or their esters of C3 to C20 straight chain dicarboxylic acids;the mono, di, and tri esters of O-acetylcitric acid or O-propionylcitricacid or O-butyrylcitric acid with C1 to C10 straight and branched chainaliphatic alcohols; the mono, di, and tri esters of citric acid with C1to C10 straight and branched chain aliphatic alcohols; and omega-3 fattyacids or esters thereof; with a large number of established and newactive agents.

In another aspect of the invention, the gel formulations generallycontain about 20% to about 80% of an LSBB excipient, and liquidformulations generally contain about 30% to about 99.9% of an LSBBexcipient. These proportions depend on the nature (e.g., solubility) ofthe particular active agent and the particular LSBB excipient. It shouldbe noted that the active agent and the LSBB excipient provides thesustained release of the active agent, rather than additional excipients(e.g., coatings) or delivery vehicles (e.g., structures).

Examples of excipients that may be useful as biocompatible,biodegradable and/or bioerodible excipients in the present invention, asdetermined by one of ordinary skill in the art in light of thisspecification, without undue experimentation, include, but are notlimited to d-α-tocopherol; d,l-α-tocopherol; d-β-tocopherol;d,l-β-tocopherol; d-η-tocopherol; and d,l-η-tocopherol (includingacetate); tocotrienol isomers, and their esters, tocotrienol isomers;the mono, di, and tri esters of O-acetylcitric acid or O-propionylcitricacid or O-butyrylcitric acid with C1 to C10 straight and branched chainaliphatic alcohols, the mono, di, and tri esters of citric acid with C1to C10 straight and branched chain aliphatic alcohols; and omega threefatty acids and their esters.

Further regarding tocopherols, this biodegradable/biocompatibleexcipient useful in the present invention refers to the family oftocopherols and tocotrienols and derivatives thereof. Tocopherols andtocotrienols are derivatives of the simplest tocopherol,6-hydroxy-2-methyl-2-phytylchroman. Tocopherols are also known as afamily of natural or synthetic compounds commonly called Vitamin E.Alpha-tocopherol is the most abundant and active form of this class ofcompounds. Other members of this class include β-, γ-, and δ-tocopherolsand α-tocopherol derivatives such as tocopheryl acetate, succinate,nicotinate, and linoleate, but the latter derivatives may have limitedsolubility that renders them unsuitable for some formulations. Usefultocotrienols include d-δ-tocotreinols, and d-β-, d-γ-tocotrienols, andtheir esters. In particular, the tocopherols and their esters of lowwater solubility, notably α-tocopheryl acetate, are exceptional vehiclesfor biocompatible nonirritating topical eye drop formulations thatprovide sustained release of pharmaceutical agents for periods up to oneweek from a single application, without interfering with vision.

In another aspect of the invention, a low solubility active agent may becombined with a biodegradable, biocompatible excipient of highersolubility to result in a LSBB formulation. For example, dimethylsulfone may be used as a binder in a LSBB formulation of a limitedsolubility active agent. Hence, the use of a soluble excipient in a LSBBformulation is within the scope of the present invention.

In yet another aspect of the invention, a surfactant may also beincluded in the formulation, particularly when the active agent is in anaqueous solution or state. For example, TPGS is a pharmaceuticallyapproved surfactant constructed from lipophilic α tocopherol attached tohydrophilic PEG 1000 through a succinate linkage. TPGS may be used intocopherol formulations (such as dl-α tocopheryl acetate) in which theaqueous component exceeds about 0.5% (wt). For example, a stable mixtureof saline and α tocopheryl actetate (EA) may be prepared (for example,by sonication) in ratios ranging from about 1:2 to 1:4 (saline:EA).Similarly, water and EA may be prepared in stable formulations at ratiosranging from about 1:2 to 1:4 (H₂O:EA) with TPGS added at about 2.5% asan emulsifier. These emulsions are stable, and suitable foraqueous-based active agents.

Any pharmaceutically acceptable form of the active agents of the presentinvention may be employed in the practice of the present invention,e.g., the free base or a pharmaceutically acceptable salt or esterthereof. Pharmaceutically acceptable salts, for instance, includesulfate, lactate, acetate, stearate, hydrochloride, tartrate, maleate,citrate, phosphate, and the like.

The active agents may also be used in combination with pharmaceuticallyacceptable carriers in additional ingredients such as antioxidants,stabilizing agents, and diffusion enhancers. For example, where wateruptake by the active agent is undesired, the active agent can beformulated in a hydrophobic carrier, such as a wax or an oil, that wouldallow sufficient diffusion of the active agent from the system. Suchcarriers are well known in the art.

Examples of proteins and proteinaceous compounds which may be formulatedand employed in the delivery system according to the present inventioninclude those proteins which have biological activity or which may beused to treat a disease or other pathological condition. They include,but are not limited to antibodies, growth hormone, Factor VIII, FactorIX and other coagulation factors, chymotrypsin, trysinogen,alpha-interferon, beta-galactosidase, lactate dehydrogenase, growthfactors, clotting factors, enzymes, immune response stimulators,cytokines, lymphokines, interferons, immunoglobulins, retroviruses,interleukins, peptides, somatostatin, somatotropin analogues,somatomedin-C, Gonadotropic releasing hormone, follicle stimulatinghormone, luteinizing hormone, LHRH, LHRH analogues such as leuprolide,nafarelin and geserelin, LHRH agonists and antagonists, growth hormonereleasing factor, callcitonin, colchicines, gonadotropins such aschorionic gonadotropin, oxytocin, octreotide, somatotropin plus andamino acid, vasopressin, adrenocorticotrophic hormone, epidermal growthfactor, prolactin, somatotropin plus a protein, cosyntropin, lypressin,polypeptides such as thyrotropin releasing hormone, thyroid stimulationhormone, secretin, pancreozymin, enkephalin, glucagons, and endocrineagents secreted internally and distributed by way of the bloodstream.

Other agents, such as α₁ antitrypsin, insulin, glucagon-like-peptides,and other peptide hormones, botulinum toxins (Botox®, Allergan, Inc.),adrenal cortical stimulating hormone, thyroid stimulating hormone, andother pituitary hormones, interferons such as α, β, and δ interferon,erythropoietin, growth factors such as GCSFm GM-CSF, insulin-like growthfactor 1, tissue plasminogen activator, CF4, dDAVP, tumor necrosisfactor receptor, pancreatic enzymes, lactase, interleukin-1 receptorantagonist, interleukin-2, tumor suppresser proteins, cytotoxicproteins, viruses, viral proteins, recombinant antibodies, portions ofantibodies, and antibody fragments and the like may be used. Analogs,derivatives, antagonists, agonists, and pharmaceutically acceptablesalts of the above may also be used.

The protein compounds useful in the formulations of the presentinvention can be used in the form of a salt, preferably apharmaceutically acceptable salt. Useful salts are known to thoseskilled in the art and include salts with inorganic acids, organicacids, inorganic bases, or organic bases.

Other active agents encompassed in the present invention includeprodrugs. Because prodrugs are known to enhance numerous desirablequalities of pharmaceuticals (e.g., solubility, bioavailability,manufacturing, etc.) the pharmaceutical dosage forms of the presentinvention may contain compounds in prodrug form. Thus, the presentinvention is intended to cover prodrugs of the presently claimed activeagents, methods of delivering the same, and compositions containing thesame.

Analogs, such as a compound that comprises a chemically modified form ofa specific compound or class thereof, and that maintains thepharmaceutical and/or pharmacological activities characteristic of saidcompound or class, are also encompassed in the present invention.Similarly, derivatives such as a chemically modified compound whereinthe modification is considered routine by the ordinary skilled chemist,such as an ester or an amide of an acid, protecting groups, such as abenzyl group for an alcohol or thiol, and tert-butoxycarbonyl group

Active agents, or active ingredients, or beneficial agents, that may beuseful in the present invention singly or in combination, as determinedby one of ordinary skill in the art in light of this specificationwithout undue experimentation, include but are not limited to thefollowing agents and the pharmaceutically acceptable salts thereof:

Angiostatic and/or Anti-inflammatory Steroids such as anecortive acetate(Retaane®, Alcon, Inc., Fort Worth, Tex.); tetrahydrocortisol;4,9(11)-pregnadien-17α,21-diol-3,20-dione (Anecortave) and its-21-acetate salt; 11-epicortisol; 17α-hydroxyprogesterone;tetrahydrocortexolone; cortisona; cortisone acetate; hydrocortisone;hydrocortisone acetate; fludrocortisone; fludrocortisone acetate;fludrocortisone phosphate; prednisone; prednisolone; prednisolone sodiumphosphate; methylprednisolone; methylprednisolone acetate;methylprednisolone, sodium succinate; triamcinolone;triamcinolone-16,21-diacetate; triamcinolone acetonide and its-21-acetate, -21-disodium phosphate, and -21-hemisuccinate forms;triamcinolone benetonide; triamcinolone hexacetonide; fluocinolone andfluocinolone acetate; dexamethasone and its 21-acetate,-21-(3,3-dimethylbutyrate), -21-phosphate disodium salt,-21-diethylaminoacetate, -21-isonicotinate, -21-dipropionate, and-21-palmitate forms; betamethasone and its -21-acetate, -21-adamantoate,-17-benzoate, -17,21-dipropionate, -17-valerate, and -21-phosphatedisodium salts; beclomethasone; beclomethasone dipropionate;diflorasone; diflorasone diacetate; mometasone furoate; andacetazolamide (Diamox®, Lederle Parenterals, Inc., Carolina, PuertoRico; several other manufacturers);

Anti-neovascularization Steroids such as21-nor-5β-pregnan-3α,17α,20-triol-3-acetate;21-nor-5α-pregnan-3α,17α,20-triol-3-phosphate;21-nor-5β-pregn-17(20)en-3α,16-diol; 21-nor-5β-pregnan-3α,17β,20-triol;20-acetamide-21-nor-5α-pregnan-3α,17α-diol-3-acetate; 3βacetamido-5β-pregnan-11β,17α,21-triol-20-one-21-acetate;21-nor-5α-pregnan-3α,17β,20-triol;21α-methyl-5β-pregnan-3α,11β,17α,21-tetrol-20-one-21-methyl ether;20-azido-21-nor-5β-pregnan-3α,17α-diol;20(carbethoxymethyl)thio-21-nor-5β-pregnan-3α,17α-diol;20-(4-fluorophenyl)thio-21-nor-5β-pregnan-3α, 17α-diol;16α-(2-hydroxyethyl)-17β-methyl-5β-androstan-3α, 17αdiol;20-cyano-21-nor-5β-pregnan-3α,17α-diol;17α-methyl-5β-androstan-3α,17β-diol; 21-nor-5β-pregn-17(20)en-3α-ol;21-or-5β-pregn-17(20)en-3α-ol-3-acetate;21-nor-5-pregn-17(20)-en-3α-ol-16-acetic acid 3-acetate;3β-azido-5β-pregnan-11β,17α,21-triol-20-one-21-acetate; and5β-pregnan-11β,17α,21-triol-20-one; 4-androsten-3-one-17β-carboxylicacid; 17α-ethynyl-5(10)-estren-17β-ol-3-one; and17α-ethynyl-1,3,5(10)-estratrien-3,17β-diol;

Nonsteroidal Anti-inflammatories such as naproxin; diclofenac; celecoxib(Celebrex®, Pfizer); sulindac; diflunisal; piroxicam; indomethacin;etodolac; meloxicam; ibuprofen; ketoprofen; r-flurbiprofen (MyriadGenetics, Inc.); mefenamic; nabumetone; tolmetin, and sodium salts ofeach of the foregoing; ketorolac bromethamine; ketorolac tromethamine(Acular®, Allergan, Inc.); choline magnesium trisalicylate; rofecoxib;valdecoxib; lumiracoxib; etoricoxib; aspirin; salicylic acid and itssodium salt; salicylate esters of α,β,γ-tocopherols and tocotrienols(and all their d, l, and racemic isomers); methyl, ethyl, propyl,isopropyl, n-butyl, sec-butyl, t-butyl, esters of acetylsalicylic acid;tenoxicam; aceclofenac; nimesulide; nepafenac; amfenac; bromfenac;flufenamate; and phenylbutazone;

Angiogenesis Inhibitors such as squalamine, squalamine lactate (Evizon™,Genaear Corp.) and curcumin; Vascular endothelial growth factor (VEGF)inhibitors including pegaptanib (Macugen®, Eyetech/Pfizer), bevacizumab(Avastin®, Genentech, Inc.), concentrated shark cartilage extract(Neovastat®, Eterna Zentaris), PTK 787 (vatalanib, ScheringAG/Novartis), ribozyme anti-angiogenic (Angiozyme®, Sirma Therapeutics,Inc./Chiron Corp.); AZD 6474 (Zactima®, AstraZeneca AB Ltd.),anti-angiogenesis chimeric monoclonal antibody specific VEGF receptor 2(IMC-1C11, ImClone Sys. Inc.), isocoumarin2-(8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl) propionic acid (NM-3,Ilex Oncology Inc,), SU668 (Pfizer),isopropoxymethyl-12-(3-hydroxypropyl) ideno[2,1-a]pyrro[3,4-c]carbazole-5-one (CEP-5214, Cephalon), CEP-7055 (the N,N-dimethyl glycine esterprodrug of CEP-5214, Cephalon), and PTC299 (PTC Therapeutics); Integrinantagonists such as anti-α_(v)β₃ antibody (Vitaxin®, Medimmune Inc.);RDG peptide mimetics such as S137 and S247 (Pfizer), conformationallyconstrained bicyclic lactam Arg-Gly-Asp-containing pseudopeptides suchas ST1646 (Sigma Tau S.p.A.); DPC A803350 (Bristol-Myers Squibb), ando-guanidines (3D Pharmaceuticals Inc.); matrix metalloproteinaseinhibitors such as prinomastat (AG 3340, Pfizer), (ISV-616, InSiteVision), (TIMP-3, NIH); S3304 (Shionogi); BMS 275291(Celltech/Bristol-Myers Squibb); SC 77964 (Pfizer); ranibizumab(Lucentis®, Genentech, Inc.); ABT 518 (Abbott Labs.); CV 247 (IvyMedical); NX-278-L anti-VEGF aptamer (EyeTech Pharm.); 2′-O-mrthoxyethylantisense C-raf oncogene inhibitor (ISIS-13650, Isis Pharm., Inc./iCoTherapeuticals, Inc.); vitronectin and osteopontin antagonists (3DPharm.); combretstatin A-4 phosphate (CA4P, OxiGene, Inc.); fab fragmentα-V/β-1 integrin antagonist (Eos-200-F, Protein Design Labs); α-v/β-3integrin antagonist (Abbott Labs.); urokinase plasminogen activatorfragment (A6, Angstrom Pharm.); VEGF antagonists (including AAV-PEDF,Chiron Corp.; VEGF-R, Johnson & Johnson/Celltech; SU10944, Sugen/Pfizer;VEGF-TRAP, Regeneron; SP-(V5.2)C, Supratek Pharm. Inc.; endostatin VEGFantagonist, EntreMed, Inc. (Rockville, Md.); kdr tyrosine kinaseinhibitor (EG-3306, Ark Therapeutics); cytochalasin E (NIH);kallikrinin-binding protein (Medical Univ, SC); combretastatin analog(MV-5-40, Tulane); pigment-epithelium derived growth factor (Med. Univ.SC); AdPEDF, GenVec, Inc.); plasminogen kringle (Medical Univ. SC);rapamycin; cytokine synthesis inhibitor/p38 mitogen-activated proteinkinase inhibitor (SB-220025, GlaxoSmithKline); FGF1 receptorantagonist/tyrosine kinase inhibitor (Pfizer/Sugen); bradykinin B1receptor antagonist (B-9858, Cortech, Inc.);bactericidal/permeability-increasing protein (Neuprex®, Xoma Ltd.);protein kinase C inhibitor (Hypericin, Sigma-Aldrich, St. Louis, Mo.);ruboxistaurinn mesylate (LY-333531, Eli Lilly & Co.); polysulphonic acidderivatives (Fuji Photo Film); growth factor antagonists such asTBC-2653 and TBC-3685 (Texas Biotech. Corp.); Tunica internalendothelial cell kinase (Amgen Inc.);

Anti-bacterials including aztreonam; cefotetan and its disodium salt;loracarbef; cefoxitin and its sodium salt; cefazolin and its sodiumsalt; cefaclor; ceftibuten and its sodium salt; ceftizoxime; ceftizoximesodium salt; cefoperazone and its sodium salt; cefuroxime and its sodiumsalt; cefuroxime axetil; cefprozil; ceftazidime; cefotaxime and itssodium salt; cefadroxil; ceftazidime and its sodium salt; cephalexin;cefamandole nafate; cefepime and its hydrochloride, sulfate, andphosphate salt; cefdinir and its sodium salt; ceftriaxone and its sodiumsalt; cefixime and its sodium salt; cefpodoxime proxetil; meropenem andits sodium salt; imipenem and its sodium salt; cilastatin and its sodiumsalt; azithromycin; clarithromycin; dirithromycin; erythromycin andhydrochloride, sulfate, or phosphate salts ethylsuccinate, and stearateforms thereof, clindamycin; clindamycin hydrochloride, sulfate, orphosphate salt; lincomycin and hydrochloride, sulfate, or phosphate saltthereof; tobramycin and its hydrochloride, sulfate, or phosphate salt;streptomycin and its hydrochloride, sulfate, or phosphate salt;vancomycin and its hydrochloride, sulfate, or phosphate salt; neomycinand its hydrochloride, sulfate, or phosphate salt; acetyl sulfisoxazole;colistimethate and its sodium salt; quinupristin; dalfopristin;amoxicillin; ampicillin and its sodium salt; clavulanic acid and itssodium or potassium salt penicillin G; penicillin G benzathine, orprocaine salt; penicillin G sodium or potassium salt; carbenicillin andits disodium or indanyl disodium salt; piperacillin and its sodium salt;ticarcillin and its disodium salt; sulbactam and its sodium salt;moxifloxacin; ciprofloxacin; ofloxacin; levofloxacins; norfloxacin;gatifloxacin; trovafloxacin mesylate; alatrofloxacin mesylate;trimethoprim; sulfamethoxazole; demeclocycline and its hydrochloride,sulfate, or phosphate salt; doxycycline and its hydrochloride, sulfate,or phosphate salt; minocycline and its hydrochloride, sulfate, orphosphate salt; tetracycline and its hydrochloride, sulfate, orphosphate salt; oxytetracycline and its hydrochloride, sulfate, orphosphate salt; chlortetracycline and its hydrochloride, sulfate, orphosphate salt; metronidazole; rifampin; dapsone; atovaquone; rifabutin;linezolide; polymyxin B and its hydrochloride, sulfate, or phosphatesalt; sulfacetamide and its sodium salt; minocycline; andclarithromycin;

Anti-infective Agents such as 2,4-diaminopyrimidines (e.g., brodimoprim,tetroxoprim, trimethoprim); nitrofurans (e.g., furaltadone, furazoliumchloride, nifuradene, nifuratel, nifurfoline, nifurpirinol,nifurprazine, nifurtoinol, nitrofuirantoin); quinolones and analogs(e.g., cinoxacin, ciprofloxacin, clinafloxacin, difloxacin, enoxacin,fleroxacin, flumequine, gatifloxacin, grepafloxacin, lomefloxacin,miloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin,oxolinic acid, pazufloxacin, pefloxacin, pipemidic acid, piromidic acid,rosoxacin, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin,trovafloxacin); sulfonamides (e.g., acetyl sulfamethoxypyrazine,benzylsulfamide, chloramine-b, chloramine-t, dichloramine t,n²-formylsulfisomidine, n⁴-β-d-glucosylsulfanilamide, mafenide,4′-(methylsulfamoyl) sulfanilanilide, noprylsulfamide,phthalylsulfacetaride, phthalylsulfathiazole, salazosulfadimidine,succinylsulfathiazole, sulfabenzamide, sulfacetamide,sulfachlorpyridazine, sulfachrysoidine, sulfacytine, sulfadiazine,sulfadicramide, sulfadimethoxine, sulfadoxine, sulfaethidole,sulfaguanidine, sulfaguanol, sulfalene, sulfaloxic acid, sulfamerazine,sulfameter, sulfamethazine, sulfamethizole, sulfamethomidine,sulfamethoxazole, sulfamethoxypyridazine, sulfametrole,sulfamidochrysoidine, sulfamoxole, sulfanilamide,4-sulfanilamidosalicylic acid, n⁴-sulfanilylsulfanilamide,sulfanilylurea, n-sulfanilyl-3,4-xylamide, sulfanitran, sulfaperine,sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfapyridine,sulfasomizole, sulfasymazine, sulfathiazole, sulfathiourea,sulfatolamide, sulfisomidine, sulfisoxazole); sulfones (e.g.,acedapsone, acediasulfone, acetosulfone sodium, dapsone,diathymosulfone, glucosulfone sodium, solasulfone, succisulfone,sulfanilic acid, p-sulfanilylbenzylamine, sulfoxone sodium,thiazolsulfone); and others (e.g., clofoctol, hexedine, methenamine,methenamine anhydromethylene-citrate, methenamine hippurate, methenaminemandelate, methenamine sulfosalicylate, nitroxoline, taurolidine, andxibomol); moxifloxacin; and gatifloxacin;

Antivirals such as amprenavir; interferon alfa-n3; interferon alfa-2b;interferon alfacon-1; peginterferon alfa-2b; interferon alfa-2a;lamivudine; zidovudine; amadine (Symmetrel®, Endo Pharm. Inc.) and itshydrochloride, sulfate, and phosphate salts, indinavir and itshydrochloride, sulfate, or phosphate salt; ganciclovir; ganciclovirsodium salt; famciclovir; rimantadine and its hydrochloride, sulfate, orphosphate salt; saquinavir mesylate; foscarnet; zalcitabine; ritonavir;ribavirin; zanamivir; delavirdine mesylate; efavirenz; amantadine andits hydrochloride, sulfate, or phosphate salt; palivizumab; oseltamivirand its hydrochloride, sulfate, or phosphate salt; abacavir and itshydrochloride, sulfate, or phosphate salt; valganciclovir and itshydrochloride, sulfate, or phosphate salt; valacyclovir and itshydrochloride, sulfate, or phosphate salt; didanosine; nelfinavirmesylate; nevirapine; cidofovir; acyclovir; trifluridine; penciclovir;zinc oxide; zinc salicylate; zinc salts of all isomers of tocopherolhemisuccnic acid; zinc salts of straight, branched, saturated, andunsaturated chain C₂ to C₂₀ aliphatic carboxylic acids; zinc pyruvate;zinc lactate; zinc ester complexes; and zinc acetoacetonate or zincacetoacetic ester complexes;

Insulins such as Novolog® (insulin aspart [rDNA origin]) and Novolin®products (Novo Nordisk Inc.); Humalog® (insulin lispro [rDNA origin]),Humalog® 75/25 and 50/50 (mixtures of insulin lispro protaminesuspension and insulin lispro), and Humulin® products (regular humaninsulin [rDNA origin], Eli Lilly & Co.); Lantus® (insulin glargine[rDNAorigin], Sanofi Aventis U.S. LLC); porcine and bovine insulins;

Glucagon-like Peptide-1 (Glp1) and analogs (for diabetes therapy andappetite suppression, cardiac protection) (see Keiffer et al., 20 EndocrRev., 876-913 (1999) such as liraglutide (Novo Nordisk Inc.); Glp1receptor stimulators such as such as Byetta® products (exenatide, andincretin mimetic, Amylin Pharm., Inc./Eli Lilly & Co.) and ZP-10(Zealand Pharma A/S); Glp-1-albumin (ConjuChem Inc.); and Dpp-IVinhibitors (which inhibit enzyme attack on Glp-1) such as Galvus®(vildagliptin, formerly LAF237, Novartis), Januvia® sitagliptin,formerly MK-0431, Merck & Co.); saxagliptin (formerly BMS-477188,Bristol-Myers Squibb), and GSK23A (GlaxoSmithKline);

Alpha Androgenergic Agonist such as brimonidine tartrate;

Beta Adrenergic Blocking Agents (Beta blockers) such as betaxolol(Betoptic®, Betoptic® S betaxolol hydrochloride suspension, Alcon Labs.,Inc.), and its hydrochloride, sulfate, or phosphate salt; levobetaxololand its hydrochloride, sulfate, or phosphate salt; and timolol maleate(Timoptic®, Timoptic-XE®, timolol maleate ophthalmic gel-formingsolution, Merck & Co.), levobunolol (Betagan®, levobunolol hydrochlorideophthalmic solution, Allergan), carteolol (Ocupress®, carteololhydrochloride ophthalmic solution, CIBA Vision Sterile Mfg./NovartisOphthalmics), metipranolol (OptiPranolol®, metipranolol ophthalmicsolution, Bausch & Lomb);

Carbonic Anhydrase Inhibitors such as brinzolamide (Azopt®, brinzolamidehydrochloride, Alcon Labs., Inc.), dorzolamide (Trusopt®, dorzolamidehydrochloride, Merck & Co.), and its drochloride, sulfate, or phosphatesalt; and dichlorphenamide (Merck);

Sympathomimtics such as epinephrine-like dipivefrin (Propine®,dipivefrin hydrochloride, Allergan), and clonodine-like bimonidine(Alphagan®, brimonidine tartrate, Allergan) and apraclonidine(Iopidine®, aprapclonidine hydrochloride, Alcon);

Mast Cell Stabilizers such as pemirolast (Alamast® pemirolast potassiumophthalmic solution, Vistakon Pharma., LLC), and its potassium salt;nedocromil ophthalmic (Alocril®, Allergan, Inc.) and its sodium salt;cromolyn and its sodium salt (PendoPharm);

Mioties (Cholinesterase Inhibitors) such as demecarium bromide,pilocarpine (Isopto Carpine, Ocusert Pilo);

Prostaglandins and prostaglandin alalogs such as bimatoprost (Lumigan®bimatoprost ophthalmic solution, Allergan); travoprost (Travatan®travoprost ophthalmic solution, Alcon Inc.); and latanoprost (Xalatan®latanaprost ophthalmic solution, Pfizer);

Antihistamines such as olopatadine and its hydrochloride, sulfate, orphosphate salt forms; fexofenadine and its hydrochloride, sulfate, orphosphate salt; azelastine and its hydrochloride, sulfate, or phosphateforms; diphenhydramine and its hydrochloride, sulfate, or phosphateforms; and promethazine and its hydrochloride, sulfate, or phosphateforms;

Antimicrotubule Agents such as Taxoids including paclitaxel (Taxol®,Bristol-Myers Squibb); vincristine (Oncovin®, Eli Lilly & Co.) and itshydrochloride, sulfate, or phosphate salt forms; vinblastine (Velbe®,Eli Lilly & Co.) and its hydrochloride, sulfate, or phosphate salt;vinorelbine (Navelbine®, Fabre Pharm. Inc.); colchicines; docetaxel(Taxotere®, Sanofi-Aventis U. S. LLC); RPR-109881 (Sanofi-Aventis); LIT976 (Sanofi-Aventis); BMS 188797 and BMS 184476 (Bristol-Myers Squibb);DJ 927 (Daiichi Pharm. Inc.); DHA-paclitaxel (Taxoprexin®, Protarga,Inc.); Epothilones including epothiloneB such as patupilone (EPO 906,Novartis/generic), BMS 247550 and BMS-310705 (Bristol-Myers Squibb),epothilone D (KOS 862, Kosan Biosci. Inc.), and ZK EPO (Schering AG);

Antineoplastic agents such as doxorubicin and its hydrochloride,sulfate, or phosphate salt; idarubicin and its hydrochloride, sulfate,or phosphate salt; daunorubicin and its hydrochloride, sulfate, orphosphate salt: dactinomycin; epirubicin and its hydrochloride, sulfate,or phosphate salt; dacarbazine; plicamycin; mitoxantrone (Novantrone®,EMD Serono Inc.) and its hydrochloride, sulfate, or phosphate salt;valrubicin; cytarabine; nilutamide; bicalutamide; flutamide;anastrozole; exemestane; toremifene; femara; tamoxifen and tamoxifencitrate; temozolomide (Temador, Schering-Plough Corp.); gemcitabine andits hydrochloride, sulfate, or phosphate salt; topotecan and itshydrochloride, sulfate, or phosphate salt; vincristine and itshydrochloride, sulfate, or phosphate salt; liposomal vincristine (TevaPharm.); methotrexate and methotrexate sodium salt; cyclophosphamide;estramustine sodium phosphate; leuprolide and leuprolide acetate:goserelin and goserelin acetate; estradiol; ethinyl estradiol; Menest®esterified estrogens (Monarch Pharm., Inc.); 5-flurouracil; bortezamib(Velcade®, Millennium Pharm., Inc.);

Antiapoptotics such as desmethyldeprenyl (DES, RetinaPharma Tech., Inc.,Philadelphia, Pa.);

Aldose Reductase Inhibitors such as GP-1447 (Grelan); NZ-314 (parabanicacid derivative, Nippon Zoki); SG-210 (Mitsubishi Pharm/Senju); andSJA-7059 (Senju);

Antihypertensives such as candesartan cilexetil (Atacand®, Takeda Pharm.Co./AstraZeneca AB); losartan (Cozaar® and Hyzaar®, Merck & Co.); andlisinopril (Zestril®, AstraZeneca AB and Prinivil®, Merck & Co.);

Antioxidants such as benfotiamine (Albert Einstein College Med./WorWagPharma); ascorbic acid and its esters; tocopherol isomers and theiresters; and raxofelast (IRFI 016, metabolized to IRFI 005, BiomedicaFoscama);

Vitrectomy Agents such as hyaluronidase (Vitrase®, ISTA Pharm., Inc.);

Adenosine Receptor Antagonist such as A2B adenosine receptor antagonist(ATL-754, Adenosine Therapeutics, LLC);

Adenosine Deaminase Inhibitor such as pentostatin (Nipent®, SuperGenInc.);

Glycosylation Antagonists such as pyridoxamine (Pyridorin™, NephroGenexInc.);

Topoisomerase Inhibitors such as doxorubicin (Adriamycin®, Pfizer;Caelyx™ Schering-Plough Pharm.; Doxil®, Johnson &Johnson/Pharmacia/generics); daunorubicin (DaunoXome®, Gilead Sci.);etoposide (Vepesid® and Etopophos®, Bristol-Myers Squibb); idarubicin(Idamycin PFS®, Pfizer); irinotecan (Camptosar®), Pfizer); topotecan(Hycamtin®, GlaxoSmithKline); epirubicin (Ellence®, Pfizer); andraltitrexed (Tomudex®, AstraZeneca);

Anti-metabolites such as methotrexate (generic) and its sodium salt;5-fluorouracil (Adrucil®, Teva Pharm. U.S.); cytarabine (Cytosar®,Upjohn Co.); fludarabine (Fludara®, Bayer HealthCare Pharm.) and itsforms as salts with acids; gemcitabine (Gemzar®, Eli Lilly & Co.);capecitabine (Xeloda®, Roche Labs. Inc.); and perillyl alcohol (POH,Endorex);

Therapeutic Antibodies including Herceptin® (trastuzumab, Genentech.Inc.). MDX-H210 (Medarex, Inc.); SGN-15 (Seattle Genetics); H11(Viventia); Therex (Antisoma); rituximan (Rituxan®, Genentech); Campath(ILEX Oncology/Millennium/Shering); Mylotarg (Celltech/Wyeth); Zevalin(IDEC Pharmaceuticals/Schering); tositumomab (Bexxar®, GlaxoSmithKline);epratuzumab (Lymphocide, Immunomedics/Amgen); Oncolym® (TechnicloneCorp./Schering AG); Mab Hu1D10 antibody (Protein Design Laboratories);ABX-EGF (Abigenix); infleximab (Remicade®, Centocor) and etanercept(Enbrel®, Wyeth-Ayerst);

Tyrosine Kinase Inhibitors/Epidermal Growth Factor Receptor Inhibitorssuch as gefitinib (Iressa, AstraZeneca, ZD 1839); trastuzumab(Herceptin®, Genentech); erlotinib (Tarceva, OSI Pharmaceuticals, OSI774); cetuximab (Erbitux, Imclone Systems, IMC 225); and pertuzumab(Omnitarg, Genentech, 2C4);

Cytotoxins such as Irofulven (MGI 114, MGI Pharma);

Neurotensin Antagonist such as SR 48692 (Sanofi-Synthelabo);

Peripheral Sigma Ligands such as SR 31747 (Sanofi-Synthelabo);

Endothelin ETA/Receptor Antagonists such as YM-598 (Yamanouchi); andatrasentan (ABT-627, Abbott);

Anti-glaucoma Agents such as prostaglandins: latanoprost, bimaloprost,travoprost; dorzolamide (Cosopt™ dorzolamide hydrochloridehydrochloride-timolol maleate ophthalmic solution, Merck); β blockers:timolol (acid-free and amine salts forms), levobunolol, betaxolol(Kerlone® beta-adrenergic blocking agent, Sanofi-Aventis), and itshydrochloride, sulfate, phosphate salts; atenolol; a 2-adrenergicantagonists: brimonidine; sympathmimetics: epinephrine, dipivetrin;miotic agents: philicarpine; carbonic anhydrase inhibitors; dorzolamide,brinzolamide, acetolamide; and chlorthalidone (PLIVA®, Inc., Easthanover, N.J.);

Immunsuppressive Agents such as sirolimus (rapamycin, Rapamune®,Wyeth-Ayerst); tacrolimus (FK506) (Prograf®, Astella Pharma US, Inc.);and cyclosporins;

Nucleic acids such as small interfering NAs (siRNA) or KA interference(RNAi), particularly, for example siRNAs that interfere with VEGFexpression; antisense oligonucleotides such as Affinitac (IsisPharma./Eli Lilly & Co.); and Genasence (Genta/Aventis);

Additional active agents include triamcinolone-16,21-diacetate;triamcinolone acetonide; fluocinolone acetonide; dexamethasone;dexamethasone-21-acetate; dexamethasone-21-(3,3-dimethylbutyrate);dexamethasone-21-phosphate disodium salt;dexamethasone-21-diethylaminoacetate; dexamethasone-21-isonicotinate;dexamethasone -21-dipropionate; dexamethasone-21-palmitate;betamethasone; betamethasone-21-acetate; betamethasone-21-adamantoate;betamethasone-17-benzoate; betamethasone-17,21-dipropionate;betamethasone-17-valerate; betamethasone-21-phosphate disodium salt;naproxen; diclofenac; celecoxib; rofecoxib; valdecoxib; etoricocib;lumiracoxib; pegaptanib octasodium; 2-methoxyestradiol; combretstatinA-4 phosphate (CA4P, Oxigene); urokinase plasminogen activator fragment(A6, Angstrom Pharm.); bradykinin B1 receptor antagonist (B-9858,Cortech); acetylcysteine; mannitol; antineoplaston; humancorticotropin-releasing factor; VN40101M (Pediatric Brain TumorConsortium) everolimus; GW572016 (NCI); thalidomide; temozolomide;tariquidar; doxorubicin; dalteparin; tarceva; CC-5013 (NCI); hCRF(Xerecept® corticorelin acetate injection, Neurobiological Tech., Inc.,Emeryville, Calif.); melphalan; thiotepa; depsipeptide; erlotinib;tamoxifen; bortezomib; lenalidomide; vorinostat; temsirolimus;modifinil; enzastuarin; motexafin gadolinium; F-18-OMFD-PET (AdvancedBiochem. Compounds, Redeberg); pemetrexed disodium; ZD6474 (NCI);valproic acid; vincristine; irinotecan; PEG-interferon alpha-2b;procarbazine; lonafarnib; arsenic trioxide; GP96 (Univ. Cal., SanFrancisco, Calif.); carboplatin; cyclophosphamide; 1311-TM-601 (TransMolecular); lapatinib; O6-benzylguanine; TP-38 toxin (NCI); cilengitide;poly-ICLC (NCI); FR901228 (NCI); TransMid™ (Xenova); talabostat;ixabepilone; AEE788 (Jonson Comprehensive Cancer Center); alanosine;sorafenib; efaproxiral; carmustine; iodine I 131 monoclonal antibodyTNT-1/B (NCI, Bethesda, Md.); intratumoral TransMid™; topatecan;lomustine; phosphorus 32; 18F-fluorodeoxyglucose (Alberta Cancer Board);vinblastine; BMS-247550 (NCI); CC-8490 (NCI); IL 13-PE38QQR (Neopharm);imatib mesylate; hydroxyurea; G207 (MediGene); radiolabeled monoclonalantibody; 2-deoxyglucose; talampanel; retinoic acid; gefitinib;tipifarnib; CPT-11 (Kentuckiana Cancer Inst); rituximab; efaproxiral;PS-341 (FDA Office Orphan Prod. Devel.); capecitabine; G-CFS (NCI);vinorelbine; paclitaxel; patipilone (Norvatis); iressa; methotrexate;ABT-751 (NCI); oxaliplatin; MS-275 (NCI); trastuzumab; pertuzumab;PS-341 (NCI); 17AAG (NCI); lenalidomide; campath-1H; somatostatinanalog; resveratrol; CEP-7055 (Cephalon); CEP-5214 (Cephalon); PTC-299(PTC Therapeutics); inhibitors of hepatocyte growth factor (L2G7mAb,Galaxy Biotech); statins such as atorvastatin (Lipitor®, Pfizer),fluvastatin (Lescor®, Novartis), rosuvastatin (Crestor®, Astra Zeneca),prevastatin (Provacol®, Teva Pharm.), simvastatin (Zocar®, Merck & Co.,Inc.), lovastatin (Mevorcor®, Merck), or cervastatin (Baycol®, Bayer AG)(HMG-CoA reductase inhibitors); and Receptor tyrosine kinase inhibitors.

Those of ordinary skill in the art will appreciate that any of theforegoing disclosed active agents may be used in combination or mixturein the pharmaceutical formulations of the present invention. Suchmixtures or combinations may be delivered in a single formulation, ormay be embodied as different formulations delivered eithersimultaneously or a distinct time points to affect the desiredtherapeutic outcome. Additionally, many of the foregoing agents may havemore than one activity or have more than one therapeutic use, hence theparticular category to which they have been ascribed herein is notlimiting in any way. Similarly, various biodegradable, biocompatibleexcipients may be used in combination or in mixtures in single ormultiple formulations as required for a particular indication. Thesemixtures and combinations of active agents and excipients may bedetermined without undue experimentation by those of ordinary skill inthe art in light of this disclosure.

The formulations of the present invention may be sterilized for use bymethods known to those of ordinary skill in the art. Autoclaving ande-beam have been used in informal studies of several embodiments andhave not appeared to have significant impact. Similarly, informalstability studies indicate acceptable stability of several embodiments.Additionally, reproducibility between aliquots and lots is very good,with a standard deviation of less than five percent or better. Hence,standard pharmaceutical manufacturing techniques are readily applied tothe technologies described herein.

An example embodiment of the present invention comprises the activeagent dexamethasone and the excipient tocoperol. Dexamethasone is aglucocorticoid and typically used in the form of the acetate or disodiumphosphate ester. Glucocorticoids are adrenocortical steroids suppressingthe inflammatory response to a variety of agents that can be ofmechanical, chemical or immunological nature. Doses vary depending onthe condition treated and on the individual patient response. Inophthalmology, dexamethasone sodium phosphate (Decadron®, Merck & Co.)as a 0.1% solution has been widely used since its introduction in 1957.The ophthalmic dose depends on the condition treated, but for control ofanterior chamber inflammation the topical dose is usually around 0.5 mgper day.

For treatment following cataract surgery, or for other treatments ordiseases of the eye, an aspect of the invention provides for acomposition comprising an active agent and the LSBB excipient useful forthe treatment of iris neovascularization from cataract surgery, macularedema in central retinal vein occlusion, cellular transplantation (as inretinal pigment cell transplantation), cystiod macular edema,psaudophakic cystoid macular edema, diabetic macular edema,pre-phthisical ocular hypotomy, proliferative vitreoretinopathy,proliferative diabetic retinopathy, exudative age-related maculardegeneration, extensive exudative retinal detachment (Coat's disease),diabetic retinal edema, diffuse diabetic macular edema, ischemicophthalmopathy, chronic focal immunalogic corneal graft reaction,neovascular glaucoma, pars plana vitrectomy (for proliferative diabeticretinopathy), pars plana vitrectomy for proliferatve vitreoretinopathy,sympathetic ophthalmia, intermediate uveitis, chronic uveitis,intraocular infection such as endophthalmitis, and/or Irvine-Gasssyndrome.

Another embodiment of the invention provides formulations and uses ofthe tocopherols and/or tocotrienols and their esters with insulins forthe delivery of the insulins in the management of diabetes. Tocopherolsand/or the tocotrienols and their esters possess outstandingcapabilities to carry therapeutic agents, especially moderate molecularweight proteins such as the insulins, through the mucosa and membranesurfaces of the eye area, or through the nasolacrimal drainage system,into the body. Pillion et al., 32 Invest. Ophthalmol. & Visual Sci.3021-27 (1991). Indeed, it is contemplated that wide variety of othertherapeutic agents (such as steroids, NSAIDs, antibiotics, hormones,growth factors, anti-cancer agents, etc.) may be available for effectivedelivery formulations with the tocopherols and/or tocotrienols and theiresters via eye drops.

The present invention relates generally to the use of compounds that areliquid, of limited solubility, biocompatible and biodegradable forcontrolled and sustained release of an agent or a combination of anagents. Gel or liquid controlled-sustained release systems can befabricated by combining an excipient discussed herein and an activeagent. Systems can combine more than one of these excipients as well asmore than one beneficial agent. Gels can be produced by vortex ormechanical mixing. Liquid formulations can be made by pre-mixing in anappropriate container or mixing of the excipient and the beneficialagent at the time of administration

Another aspect of the present invention provides for embodimentscomprising omega-3 fatty acids. The health benefits of dietarysupplements of omega-3 fatty acids and their esters are well known. Theparticularly important omega-3 fatty acids in human nutrition areα-linolenic acid (ALA, C18H30O2, fw 278.4) eicosapentaenioc acid (EPA,C20H30O2, fw 306.5) and docosahexaenoic acid (DHA, C22H32O2, fw 328.5).The term omega-3 signifies that the first double bond exists between thethird and second carbon atoms counting from the terminal methyl at theopposite end of the chain from the carbonyl group.

The human body cannot synthesize EPA or DHA except by using ALA as anintermediate. But the presence of EPA and DHA in almost all tissues ofthe body indicates the importance of these compounds to the body andthus the judicious injection into the body of their therapeuticformulations will be safe, efficient and effective. These benefits alsoextend to the simple esters of EPA and DHA of the C₁ to C₈ straight andbranched chain aliphatic alcohols such as ethyl EPA and ethyl DHA.Recently, the FDA has approved ethyl EPA and ethyl DHA for dietarysupplements. One important property of these ethyl esters is that theycan be fractionally distilled from their readily available but crudesource, fish oil. This purification process provides the EPA and DHAesters free from possible heavy metal and PCB contaminants. Thus, thereremains a need for the development of these purified esters as liquidexcipient vehicles for injectable sustained drug release in variousareas of the human or animal body.

The embodiments thus provide for the novel concept of injections ofomega-3 fatty acids and their esters by themselves or as novel andtherapeutic formulations with active agents directly into strategicareas of the human or animal bodies to provide for the sustained releaseof the omega-3 compounds and therapeutic but nontoxic levels of theactive agents for periods of months to over a year.

Yet another embodiment of the present invention relates generally tonovel topically applied formulations containing both steroids andantioxidants. Specifically, the inclusion of antioxidants with steroidsaddresses the problem that many steroids have harmful side effectsarising from their being initiators of destructive oxidative andphoto-oxidative radical chain reactions. These novel steroid-antioxidantformulations are designed to be applied topically, externally for theknown steroid therapies of anti-inflammation and regulation of metabolicand immune functions, but also due to the presence of antioxidants tosuppress damaging oxidative free radical reactions initiated by thesteroids in addition to harmful oxidative chemistries normally presentin cells.

Although oxygen is required for many life sustaining metabolicreactions, it also has damaging chemistries with cellular components,involving very reactive oxygen components: superoxide radicals, hydrogenperoxide, hydroxyl radicals, and organic peroxides and hydroperoxides.Polyunsaturated lipids are important components of cells, but they aremajor substrates for oxidative attack leading to cell death. Thus, thedependence of cells on oxygen places them a precarious position betweenthe prolife and toxic chemistries of oxygen. Cells contain protectiveantioxidant molecules such as tocopherol, ascorbic acid, glutathione,melatonin, carotenes, carnitine, and others. The natural level oftocopherol in the human lens is around 2.2 μg/ml (Yeum et al., 19(6)Curr. Eye Res. 502-05 (1999)), and the ascorbate level in tears is 3.52μg/ml (Choy et al., 80(9) Optom. Vis. Sci. 632-36 (2003)). Unfortunatelythe exposure of cells to some steroids, even though for very necessarytherapeutic reasons, has been found to tip this balance towards thetoxic side. It has been demonstrated that these steroids, especially theglucocorticosteroids such as triamcinolone and dexamethasone, readilyinteract with oxygen and/or light to become initiators of damagingoxidative chain reactions. Miolo et al. 78(5) Photochem. & Photobiol.,425-30 (2003); Calza et al., 12(12) J. Am. Soc. Mass. Spectrom., 1286-95(2001). Although the co-administration of certain antioxidants withcertain steroids has been shown to ameliorate the toxic oxidativeprocesses initiated by the steroids (Kosano et al., 76(6) Exp. Eye Res.,643-48 (2001)), most commercially available injectable steroidformulations do not include antioxidants. See Fact sheet inserts forKenalog™, Bristol-Myers Squibb, 2006; Depo Medrol™, Pharmacia, 2003;Decadron™, Merck Sharp & Dohme, 1995, (contains bisulfites,hydroxybenzoate esters which might have antioxidant effects). Informulating compositions containing antioxidant supplements one must bevery careful not to add too high a level of antioxidants, however,because it has been demonstrated that at high levels many of theseantioxidants actually are pro-oxidants and may increase oxidativedamage. Bowry et al., 270 J. Biol. Chem. 5756-63 (1995); Halliwell, 25Free Rad. Res. 439-54 (1996). Using the naturally occurring antioxidantsand mimicking their levels in the cell environment would be goodpractice,

The steroid components and excipients of these novel formulations andtheir therapeutic effects are well described herein and in U.S. PatentApplication Publication No. 2008/0038316. The possible adverse effectsof the steroids used in these formulations are in many cases believed toarise from the aforementioned damaging oxidative chemistries initiatedby these steroids in the absence of proper antioxidants. The environmentof the eye is particularly damaging for it is exposed to both oxygen andlight energy. The phenolic or quinone-like structures of the steroidmolecules readily absorb UV-A and UV-B radiation to convert thesemolecules to unpaired electron radical species. These radical speciescan damage cell components (especially unsaturated lipids in cellmembranes) or they can interact with oxygen to instigate damaging peroxychain reactions leading to cataracts (Nishigori et al., 35(9) Life Sci.981-85 (1984); Boscia et al., 41(9) Invest. Ophthalmol. Vis. Sci.2461-65 (2000)), and glaucoma (Sacca et al. 84(3) Exp. Eye Res. 389-99(2007)). Cataract formation and glaucoma are maladies associated withsteroid therapies in the eye. In the case of intra-articular steroidtherapies repeated injections are avoided because they lead to cartilageand bone degeneration. Reactive oxygen species have been identified ascausative agents. Kim et al., 49(9) Free Radic. Biol. Med. 1483-93(2006).

In the context of the present formulation in which the LSBBexcipient/active agent formulation provides for the sustained release ofthe active agent, other components may be added to the formulation asare known in the art of eye drops or topical formulations. Additionally,the formulations of the present invention may be combined with othertherapies or interventions following standard acceptable best practices.

Without further elaboration, one skilled in the art having the benefitof the preceding description can utilize the present invention to thefullest extent. The following examples are illustrative only and do notlimit the remainder of the disclosure in any way.

EXAMPLES Example 1 The Assay Procedure for Measuring the ReleaseProfiles of Dexamethasone or Triamcinolone Acetonide from SustainedRelease Formulations

The vials for the release studies were labeled and the weight of eachvial was recorded. To each vial was added 3 grams-4 grams of 0.9% salinesolution and the weight was recorded. Then the formulation was injectedor placed at the bottom of the vial, The weight of the formulation wasrecorded. An additional amount of 0.9% saline solution was added to atotal of 10 grams of saline. The resulting vial was kept in an incubatoror water bath at 37° C. Samples were taken periodically to measure therelease profile of dexamethasone or triarmcinolone acetonide using aHPLC instrument. Sampling protocol was carried out according to thefollowing procedure: Using a disposable pipette, 8 grams of the salinesolution containing dexamethasone or triamcinolone acetonide waswithdrawn carefully from each vial. Eight (8) grams of 0.9% salinesolution was then added to each vial. The vials were kept at 37° C.after sampling.

The HPLC analysis was carried out using a Beckman Gold Instrument withan autosampler. Calibrators with three different concentrations ofdexamethasone or triamcinolone acetonide in water were prepared.Calibrators and samples were injected onto a C18 column (Rainin, 250×4.6mm) containing a guard column (C18, 4.6 mm×1 cm) and analyzed,respectively. The column was eluted using a mobile phase of 45% (or 50%)acetonitrile/water, flow rate 1.0 ml/min, and 7 min or 6 min run time atan ambient temperature. The detector wavelength of 238 nm was used. Thedexamethasone or triamcinolone acetonide (retention times, 6 min-4 min)concentration of each sample was calculated from the standard curveusing the software of the Beckman Gold instrument.

A wash program to clean the HPLC column was set up during the HPLC run.After every three or four injections, a sample containing 20 μl ofacetonitrile was injected onto the column, the column was eluted with amobile phase of 99% acetonitrile/water, flow rate 1 ml/min, and a runtime 7 min. Then the column was equilibrated back to the original mobilephase by injecting 20 μl of acetonitrile, eluting with 45% (or 50%)acetonitrile/water, flow rate I ml/min, and a run time 7 min.

The sampling times and the active ingredient (for example dexamethasoneor triamcinolone acetonide) concentrations determined from HPLC wererecorded and tabulated. The percent drug released and the amount of drugreleased were each calculated from a Microsoft Excel software program.

Example 2 Preparation of Mixtures of Dexamethasone in a Tocopherol andTheir Release Profiles

For the preparation of 10% dexamethasone (Dex) in d-tocopherol, oneportion by weight of Dex was mixed with nine portions by weight ofd-tocopherol. The resulting suspension was stirred at an ambienttemperature until a homologous mixture formed. The mixture was thenaliquoted and analyzed for release profile as shown in FIG. 1.

For the preparation of 20% Dex in d-tocopherol, two portions by weightof Dex was mixed with eight portions by weight of d-tocopherol. Theresulting suspension was stirred at an ambient temperature until theformation of a homologous mixture. The mixture was then aliquoted andanalyzed for release profile as shown in FIG. 1.

For the preparation of 50% Dex in dl-tocopheryl acetate, five portionsby weight of Dex were mixed with five portions by weight ofdl-tocopheryl acetate. The resulting suspension was stirred at ambienttemperature until a homologous mixture formed. The mixture was thenaliquoted and analyzed for the release profile as shown in FIG. 1.

Example 3 Omega-3 Fatty Acids and Their Esters for Liquid Sustained DrugRelease Formulations

The embodiments provide for the novel concept of formulations of omega-3fatty acids and their esters by themselves or as novel and therapeuticformulations with active agents directly into strategic areas of thehuman or animal bodies to provide for the sustained release of theomega-3 compounds and therapeutic but nontoxic levels of the activeagents for periods of months to over a year.

The process of applying small amounts of these omega-3 fatty acid/esteralone or their formulations containing active agents at the site of themalady is not only maximally effective and efficient but also avoids thewaste and potentially increased danger of systemic oral administration.These novel sustained drug release formulations of the omega-3 liquidsalone or in combination with the other excipients disclosed herein andin U.S. Patent Application Publication No. 2008/0038316 can be appliedtopically to the eye. Among a number of maladies to be treated, aslisted herein and in U.S. No. 2008/0038316, are those of the retina suchas macular degeneration, retinitis pigmentosa, proliferativevitreoretinopathy, to name a few. A potentially advantageous property ofDHA, EPA, and their esters is their importance in maintaining healthyretinal tissue and their required presence for proper development ofneonatal retinal function. See, e.g., Jeffrey et al., 36(9) Lipids859-71 (2001); SanGiovanni & Chew, 24(1) Prog Retin Eye Res. 87-138(2005); Bazan, 29(5) Trends Neurosci. 263-71 (2006); King et al., 26(17)J. Neurosci. 4672-80 (2006).

Some more specific, but not limiting, examples contemplated for oculartherapies are for inflammatory maladies of the eye. Topicaladministration may include, for example, 10 μl to 60 μl liquidmicrospheres of ethyl DHA/ethyl EPA alone or as mixtures containing 10%to 50% by weight of microcrystalline dexamethasone or triamcinoloneacetonide. This provides for the maintenance of therapeutic levels ofthe omega-3 fatty acids or the therapeutic concentration of the steroidsin the area of the eye for extended periods. In the case of anti-VEGFtherapy similar amounts of such agents as ranibizumab or bevacizumabcould be employed in a similar manner with the omega-3 excipients. Theextensive list of other beneficial agents employed for the list of awide variety of maladies are disclosed herein and in U.S. No.2008/0038316.

Example 4 Formulations Containing Steroids and Antioxidants

This embodiment relates generally to novel topically appliedformulations containing both steroids and antioxidants. Theseformulations allow the application of steroids to achieve their intendedbenefits (anti-inflammation, immune modulation) without initiation ofharmful oxidative chemistries, These example formulations are composedof one or more of the steroids listed in Group A combined with one ormore of the antioxidants listed in Group B and all dispersed ordissolved in one or more of the delivery vehicles selected from theexcipients described herein and listed in Group C and also described inU.S. No. 2008/0038316.

Group A Steroids triamcinolone dexamethasone diethyl aminoacetatetriamcinolone acetonide dexamethasone isonicotinate triamcinolonediacetate dexamethasone palmitate triamcinolone acetate prednisonetriamcinolone disodium phosphate prednisolone triamcinolonehemisuccinate prednisolone acetate triamcinolone benetonide prednisolonesodium phosphate dexamethasone methylprednisolone dexamethasone acetatemethylprednisolone acetate dexamethasone methylprednisolone disodiumphosphate sodium succinate dexamethasone 3,3- paramethasonedimethylbutyrate etrahydrocortexolone cortisone betamethasone cortisoneacetate betamethasone acetate hydrocortisone betamethasone disodiumhydrocortisone acetate phosphate tetrahydrocortisol betamethasonebenzoate fludrocortisones betamethasone valerate fludrocortisone acetatebetamethasone dipropionate fludrocortisone phosphate betamethasoneadamantoate anacortive beclomethasone anacortive acetate beclomethasonedipropionate mometasone furoate diflorasone fluocinolone diflorasonediacetate

Group B Antioxidants ascorbic acids and salts retinyl palmitate ascorbylpalmitate probucol ascorbyl dipalmitate erythorbic acid ascorbylstearate sodium erythorbate ascorbyl-2,6-dibutyrate α-lipoic acidd-tocopherol (α,β,γ,δ isomers) isocitrate dl-tocopherollutein/zeaxanthin/ (α,β,γ,δ isomers) meso-zeaxanthin the acetate,hemisuccinate, nicotinate eugenol and succinate-PEG ester derivatives ofisoeugenol the above tocopherol isomers (−)-epicatechin glutathione(−)-epigallocatechin gallate β-carotine benzyl alcohol carnitine benzylbenzoate carnitine 2,6-di-tertbutyl-4- acetate methoxy phenol transreveratrol butylated hydroxytoluene retinoic acid butylatedhydroxyanisole retinyl palmitate quercetin melatonin catechin timololrutin luteolin coenzyme Q kaempferol fisetin thyroxine methyl gallatepyrroloquinolone superoxide dismutase

Group C Exipients d-tocopherol (α,β,γ,δ isomers) dl-tocopherol (α,β,γ,δisomers) the acetate and esters of C-3 to C-10 straight and branchedchain aliphatic acids with the above tocopherol isomers dimethyl sulfone(MSM) omega-3 fatty acids and their ester with C-1 to C-10 straight andbranched chain aliphatic alcohols triethyl, tripropyl, or tribuyltri-straight and branched chain esters of O-acetyl, O-propionyl, C-1 toC-10 aliphatic alcohol or O-butyryl citrate esters of citric acid

As mentioned above, to avoid harmful pro-oxidative chemistries careshould be taken not to expose the cells to too high a level of theantioxidants. This may present a problem as formulators develop aone-shot formulation that administers steroids and antioxidants formonths to a year or more. The formulation must incorporate enoughantioxidants to last this long without releasing pro-oxidativeconcentrations. This is achieved in this embodiment of the invention byusing lipophyllic prodrug forms of the antioxidants such as ascorbylpalmitate, tocopheryl acetate, benzyl benzoate, and the like, whichslowly release the active, more hydrophyllic form into the cellularenvironment upon hydrolysis.

Examples of a sustained release formulation of this embodiment includeformulations such as:

(1) α-tocopheryl acetate 60 pts/wt ascorbyl palmitate 10 pts/wttriamcinolone acetonate 40 pts/wt (2) α-tocopheryl acetate 60 pts/wtascorbyl palmitate 10 pts/wt dexamethasone 40 pts/wt

Example 6 Sustained Release Eye Drop Formulation Containing Cyclosporin

Instillation of droplets of about 10 mg of α-tocopheryl acete (ATA) ontothe front of the eyes of human volunteers revealed that there was noirritation and the liquid quickly spread around the periphery of theanterior surface leaving vision unblurred. Inspection showed that theATA, probably because of its low water solubility, remained in the eyefor periods exceeding seven days. Subsequently, as shown in FIG. 2 andFIG. 3, formulations of ATA:cyclosporin A (Chemwerth, Woodbrigdge,Conn.) or ATA:timolol were instilled into rabbit eyes to reveal thattherapeutic levels of these active agents were continuously released tothe tears for periods of seven days. No indications of irritation wereobserved.

Regarding FIG. 2, a (45:55) by wt formulation of cyclosporin A (CSA) inATA was instilled topically as one eye drop onto one eye of two NZW 4.0kg rabbits. Droplet weighing 6.6 mg (▴) and 10.8 mg (♦) were instilled.Tear samples were collected daily by filter paper, weighed, eluted in300 μl MeOH, and analysed for CSA and ATA by LCMSMS.

Regarding FIG. 3, a (10:90) by wt formulation of timolol base(Sifavitor, Italy) in dl-α-tocopheryl acetate was instilled topically aseye one drop onto one eye of two NZW 4.0 kg rabbits. Droplets weighing4.3 mg (♦) and 6.0 mg (▴) were instilled. Tear samples were collecteddaily by filter paper, weighed, eluted in 300 μl MeOH, and analysed fortimolol base and tocopheryl acetate by LCMSMS.

Example 7 Sustained Release Eye Drop Formulation ContainingDexamethasone

Eye drop formulations included 10% or 20% dexamethasone in d-tocopherolwere prepared as follows: One portion by weight of dexamethasone wasmixed with nine portions by weight of d-tocopherol. The resultingsuspension was stirred at an ambient temperature until there was aformation of a homogeneous mixture. The mixture was then aliquoted andanalyzed for release profile. Two portions by weight of dexamethasonewere mixed with eight portions by weight of d-tocopherol. The resultingsuspension was stirred at an ambient temperature until there was aformation of a homogeneous mixture. The mixture was then aliquoted andanalyzed for release profile. For 50% dexamethasone in dl-tocopherylacetate, five portions by weight of dexamethasone were mixed with fiveportions by weight of dl-tocopheryl acetate. The resulting suspensionwas stirred at an ambient temperature until there was a formation of ahomogeneous mixture. The mixture was then aliquoted and analyzed forrelease profile, as shown in FIG. 4,

It is contemplated that novel, non-irritating, long-lasting sustaineddrug release topical eye drop formulations comprise a tocopherol oromega-3 fatty acid selected from Group A, combined with at least one ofthe active agents listed in Group B.

Group A Excipients; α, β, γ, δ tocopherols; α, β, γ, δ tocotrienols; theesters of tocopherol and tocotrienols isomers with C1 to C10 straightand branched chain aliphatic carboxylic acids (such as acetates) d, l,and dl isomers of the tocopherols, tocotrienols and their esters, forexample α tocopheryl acetate; the mono, di, and tri esters ofO-acetylcitric acid or O-propionylcitric acid or O-butyrylcitric acidwith C1 to C10 straight and branched chain aliphatic alcohols; the mono,di, and tri esters of citric acid with C1 to C10 straight and branchedchain aliphatic alcohols; and omega-3 fatty acids.

Group B Beneficial Agents, as discussed in many of the preceedingparagraphs; anti-glaucoma agents; immunsuppressive agents; angiostaticand/or anti-inflammatory steroids; nonsteroidal anti-inflammatories;anti-infective agents; anti-bacterials; antivirals; α androgenergicagonists; β adrenergic blocking agents; mast cell stabilizers;antihistamines; antimicrotubule agents; antineoplastic agents;topoisomerase inhibitors: anti-metabolites; and antibody therapeuticagents.

Example 8 Tocopherol/Latanoprost Eye Drops Intraocular Pressure in theRabbit Eye

Duplicate experiments were run in two NZW rabbits. Intraocular pressures(IOPs) were measured using Tono-Pen® tonometer (Reichert, Inc.). Eacheye of each rabbit was monitored for five days without treatment toestablish baseline values. At day 5, one drop of approximately 50 μldrops of 0.005% latanoprost in α tocopheryl acetate (EA) was placed intoone eye of each rabbit. The other eye received a drop of 0.9% NaCl inwater. IOPs were monitored for another ten days.

As shown in FIGS. 5B and 5D, the eyes treated with one drop of thelatanoprost/EA formulation exhibited a decrease in IOP that wassustained over several days as compared to the saline-treated eyes(FIGS. 5A and 5C).

Example 9 In vitro Study of Dexamethasone in Triethyl O-Acetyl Citrate(TEAC)

To 760 mg of TEAC was added 240 mg of Dexamethasone with ample stirringto form a homogeneous mixture, Six mg (25 μl) and 12 mg (25 μl)microdrops of this mixture were each incubated in 10 ml of 0.9% salineat 37° C. Periodically, 8 ml portions were withdrawn for assaying andreplaced with 8 ml of fresh 0.9% saline. The release of Dex from aformulation consisting of 24% Dex in TEAC is depicted in FIG. 6. Therelease of Dex from a formulation consisting of a 6 mg (25 μl) microdropof 20% Dex in 1:1 TEAC/Tocopheryl acetate is reflected in FIG. 7. Insummary, these results indicate that adding tocopheryl acetate to theTEAC excipient can extend the sustained release of therapeutic levels ofDex up to 450 days.

Modifications of the above described modes for carrying out theinvention that are obvious to those of ordinary skill in the surgical,pharmaceutical, or related arts are intended to be within the scope ofthe appended claims.

We claim:
 1. A method of lowering intraocular pressure in a subjectcomprising the step of: administering to the eye of a subject in needthereof an eye drop formulation consisting of prostaglandin dissolved,dispersed or suspended in tocopheryl acetate; wherein the administrationof a unit dose of a single eye drop has therapeutic effect for sevendays and administration is repeated only once every seven days.
 2. Apharmaceutical eye drops formulation for lowering intraocular pressureconsisting of timolol dissolved, dispersed or suspended in tocopherylacetate; wherein a unit dosage of one drop provides sustained release oftimolol for seven days.
 3. A method of lowering intraocular pressure ina subject comprising the step of: administering to the eye of a subjectin need thereof an eye drop consisting of timolol dissolved, dispersedor suspended in tocopheryl acetate; and wherein the administration of aunit dose of a single drop has therapeutic effect for seven days andadministration is repeated only once every seven days.
 4. Apharmaceutical eye drops formulation for lowering intraocular pressureconsisting of prostaglandin dissolved, disperse or suspended intocopheryl acetate; wherein a dosage unit of a single drop providessustained release of said prostaglandin for seven days.
 5. A dosagedispensing container comprising the pharmaceutical eye drops formulationof claim
 2. 6. A dosage dispensing container comprising thepharmaceutical eye drops formulation of claim 4.